종 설 대한생식의학회지 : 제 36 권제 3 호 2009 관동대학교의과대학 1, 제일병원산부인과 2, 불임및생식분과 3, 습관성유산클리닉 4 양광문 Roles of T Lymphocytes in Early Human Reproduction Kwang Moon Yang 4 Recurrent Miscarriage Clinic, 3 Reproductive Endocrinology and Infertility, 2 Department of Obstetrics and Gynecology, Cheil General Hospital & Women's Healthcare Center, 1 Kwandong University College of Medicine, Seoul, Korea [Korean. J. Reprod. Med. 2009; 36(3): 151-162.] 수정, 착상부터임신후반기까지영장류의생식활동은모체와태아간면역계의관용과거부의균형에의존하게되며이런면역반응은부성의 major histocompatibility complex (MHC) 를가진배아또는태아에의한면역계의자극을모체가인지함으로서시작된다. 하지만태아에대한모체의면역반응은 " 면역관용, immune tolerance" 이라는자궁특유의면역학적특징을보인다. 1950년대 Medawar 등은태아가모체내에서면역계의공격을이기고안전하게성장할수있는기전으로 i) 모체면역세포가태아항원에대한무반응 (anergy) 또는면역관용을획득한다는가설, ii) 태아와모체간해부학적장벽에의해모체면역세포가태아세포에접근할수없다는가설, 그리고 iii) 태아세포스스로동종항체의발현을억제한다는가설등을제기하였다. 1 하지만 Medawar의가설은초창기생식면역학의기본개념을제시하였지만태아항원과모체면역계사이에이루어지는면역관용현상을설명하는데는부족함이많았다. 이후, 자연살해세포 (natural 주관책임자 : 양광문, 우 ) 100-380 서울특별시중구묵정동 1-19, 관동대학교의과대학, 제일병원산부인과 Tel: (02) 2000-7545, Fax: (02) 2000-7790 e-mail: km1yang@naver.com killer, NK cell), 자연살해 T 세포 (natural killer T, NKT cell), 면역조절 T 세포 (regulatory T, Treg cell), 단핵세포 (monocyte), 수지상세포 (dendritic cell), 대식세포 (Macrophage) 등다양한종류의모체면역세포들이면역관용에관여한다는연구들이보고되었다. 2 이들면역세포들은자궁내의태아와모체가접촉하는 " 태아-모체접촉면, feto-maternal interface" 에 decidual associated lymphoid tissue (DALT) 라는임신특이의조직학적구조물내에존재하며태아에대한모체의면역관용을획득하는데중요한역할을하고, 착상및임신유지에수반되는혈관생성및영양막 (trophoblast) 의발달에필수적인무균성염증반응 (sterile inflammation) 을유발하는것으로알려졌다. 3 DALT에서모체의면역세포들과여러전달물질간의복잡하고다양한연결망의형성에의한적절한염증반응은배아의착상및임신의유지에필수적인혈관생성및영양막의발달에중요한역할을하는반면적절하지않거나과도하게오랜기간지속되는염증반응은급성혹은만성이식거부반응과유사한작용을일으켜태반의성장, 태아의성장및발달에심각한장애를초래하며착상부전 (repeated implantation failure), 습 - 151 -
대한생식의학회지 Figure 1. Classifications of T lymphocytes. T lymphocytes are classified to Tαβ and Tαδ lymphocyte by cell surface receptor (A), CD4 + /25 - T, CD4 + /25 + T, CD8 +, and Natural Killer T cell (NKT) cell by surface marker expression (B), and Th0, Th1, Th2, Th3, Tr1, Tc0, Tc1, Tc2, and CD8 + Tr by cytokine secretion (C). Th: helper T lymphocyte, Tc: cytotoxic T lymphocyte, Tr: T regulatory cell. Kwang Moon Yang. Roles of T Lymphocytes in Early Human Reproduction. Kwang Moon Yang. Roles of T Lymphocytes in Early Human Reproduction. Korean J Reprod Med 2009. 관성유산 (recurrent spontaneous abortion), 임신자간증 (preeclampsia) 등그병인이유사한생식능력장애 (defect of reproductive performance) 의원인이될수있다. 4 인간탈락막또는자궁내막에존재하는면역세포는극소수의백혈구만존재하며주로세가지아형의면역세포즉, T 림프구, 대식세포, 자궁내자연살해세포등이주를이루고 B 림프구가거의없는점등에서말초혈액의면역세포의구성과많은차이가있다. 5 이중 T 림프구는증식기자궁내막에서면역세포의약 45% 를차지하고착상시기에는약 32% 를차지하지만임신초기에는자궁내자연살해세포 (uterine NK cell) 의급격한증가에따라상대적으로약 20% 로감소하게된다. 6,7 하지만 T 림프구는착상및태아에대한모체의면역관용등생식과정전반에있어면역반응의중추적인역할을하고있으며, 이는임신중 T 림 프구를제거한경우태아의유산의증가와태반의성장결여등을보고한초기동물실험에서입증되었다. 8,9 한편 HLA-G, 억제성 T 림프구자극물질 (inhibitory T cells co-stimulatory molecules), trophoblast에서분비되는보체 (complement) 조절물질등여러가지면역조절분자들과 indoleamine 2,3 dioxygenase (IDO) 등의면역억제효소들도 semi-allogenic fetus 가면역관용을획득하는데관여하는것으로보고되었다. 10~14 본고찰에서는착상과임신유지에관련된면역세포가운데 T 림프구의종류및각각의기능에대해정리해보고자한다. T 림프구는, i) 림프구수용체의단백질구성성분, ii) 세포표면의표식자, iii) 생성되는사이토카인에따라그기능및역할이구분된다 (Figure 1). - 152 -
제 36 권제 3 호, 2009 양광문 수용체에따른 T 림프구의분류 T 림프구는세포표면에발현되는수용체의단백질구성성분, 즉, α, β, γ 및 δ polypeptide 사슬에의해 Tαβ 림프구및 Tγδ 림프구로분류되고, 이중 Tαβ 림프구가말초혈액및림프조직에서 T 림프구의약 90~95% 를차지하며 Tγδ 림프구는 5~10% 를차지한다. 15 생식과정전반부터 Tαβ와 Tγδ 림프구는두아형모두가중요한역할을하지만그작용시기및기전은서로상이하다. 즉 Tαβ 림프구는착상시기에중요한작용을하는반면, Tγδ 림프구는착상후유산을방지하는역할을하며 Tγδ 림프구가유산을방지하는기전에는 Vγ1.1δ66.3 T 림프구에서 IL-10 및 TGF-β2를생산함에기인함이동물실험을모델로보고되었다. 16,17 한편, 인간에서도말초혈액 Tγδ 림프구아형 (Vγ1Vδ1 부터 Vγ9Vδ9) 의비율이습관성유산의과거력이있는군과대조군간에차이가있다는보고가있으며, 18 탈락막에서의 Tγδ 림프구의역할을강조하는보고가있었으나, 19 Tγδ 림프구의인간생식면역에서의역할에관한증거를증명하는연구결과에대한보고는많지않은상태이다. 현재까지인간여성의탈락막내에서생식과정에관여하는 T 림프구의아형은절대적으로수적우위를가진 Tαβ 림프구로인식되고있다. 표식자의발현에따른 T 림프구의분류 T helper (CD3 + /4 +, Th cell) 림프구와 cytotoxic T (CD3 + /8 +, Tc cell) 림프구 T 림프구는 CD 3 (cluster differentiation 3) 항원을세포표면에공통적으로발현하며기타다른세포표면표식자의발현여부에따라크게 CD3 + /4 + 림프구와 CD3 + /8 + 림프구로분류되는데, CD4 + 림프구는 helper T (Th) 세포로칭하며 CD8 + 림프구는 cytotoxic T (Tc) 세포로칭한다. Lachapelle 등은임신전습관성유산환자의자궁내막조직의 T 림프구 의아형을관찰한결과 CD4 + /CD8 + 림프구의비율이정상여성에비해유의하게증가됨을볼수있었으며, 이는 CD4 + 세포의증가혹은 CD8 + 세포의감소가습관성유산의원인이될수있다고보고하였다. 20 한편 CD4 + 세포는 α-사슬 IL-2 수용체인 CD25 표식자의발현정도에따라활성화된 CD4 + 세포 (CD25 +low CD4 + ) 와조절 T 림프구 (regulatory T cell, Treg cell, CD4 + 25 +high ) 로세분되며활성화된 CD4 + 세포는자연유산및습관성유산을경험한여성의탈락막에서염색체이상에의한유산또는계획적유산을시행한대조군의탈락막과비교하여높게발현되는현상을보여, 탈락막내의 CD4 + T 세포의활성이자연유산및반복유산의원인으로제시되기도하였다. 21 조절 T 림프구 (Regulatory T, Treg cells, CD4 + / 25 + ) 말초혈액 CD4 + αβ T 림프구의아형중 CD4 표식자와 CD25 표식자를공동발현하는세포를조절 T 림프구 (Treg, CD4 + 25 + ) 라칭하며 T 림프구면역관용 (antigen-specific T-cell tolerance) 에관여한다. 조절 T 림프구 (CD4 + /25 + ) 는임신초기에에스트라디올 (estradiol) 과 TGF-β의자극에의해전구세포 (CD4 + 25 - ) 로부터유도된후, 22,23 면역억제및면역관용에핵심적인역할을수행한다. 24 조절 T 림프구는크게두가지의종류즉, 자연성조절 T 림프구 (natural T reg cell) 와적응성조절 T 림프구 (adaptive T reg cell) 로분류된다. 25 자연성조절 T 림프구는흉선에서유래하며 TGF-β, IL-10 등을분비함으로서고유의면역조절능과항염증작용을수행한다. 26 반면, 적응성조절 T 림프구는말초조직에서생성되며미성숙한수지상세포와결합하여 tryptophan 대사에필수적이고모체-태아간극에서강력한항염증작용을하는것으로잘알려진 indoleamine 2,3-deoxygenase (IDO) 라는효소를생산한다 (Figure 2). 27,28 IDO는 tryptophan 대사과정중 kynurenine pathway의 rate-limiting 효소로서 IDO 효소가증가시 tryptophan의대사가증가하며결 - 153 -
대한생식의학회지 Figure 2. A working model of the key steps in the induction and effector pathways of Treg cell activation, expansion and suppressive function to mediate maternalfetal tolerance (Modified from Guerin et al., 2009). 65 Kwang Moon Yang. Roles of T Lymphocytes in Early Human Reproduction. Korean J Reprod Med 2009. Figure 3. Molecular mechanisms of IDO-induced immunosuppression. IDO catalyzes the initial and rate-limiting step in the degradation of tryptophan along the kynurenine pathway. Tryptophan metabolites have been shown to have immunomodulatory activity, alone or in combination with the GCN2 signaling pathway. IDO enzymatic activity results in the local depletion of tryptophan and a local increase in the concentration of downstream metabolites. The decrease in tryptophan can cause a rise in the level of uncharged transfer RNA (trna) in neighboring T cells, resulting in activation of the amino acid-sensitive GCN2 stress-kinase pathway. In turn, GCN2 signaling can cause cell cycle arrest and anergy induction in responding T cells. The local increase in tryptophan metabolites can cause cell cycle arrest, apoptosis, and (in conjunction with GCN2 signaling) differentiation of new Tregs from uncommitted CD4 + T cells (Modified from Mellor et al., Mellor et al., 2004). 29 Kwang Moon Yang. Roles of T Lymphocytes in Early Human Reproduction. Korean J Reprod Med 2009. - 154 -
제 36 권제 3 호, 2009 양광문 국 tryptophan의감소와대사물질이증가를유도하여 T 림프구의세포성장을억제하고세포자멸사 (apoptosis) 를촉진시켜강력한면역억제의효과를유발한다 (Figure 3). 28,29 정상여성에서 FoxP3 + 인 Treg 세포는생리주기의난포기에그수가증가하며그증가양상은혈청에스트라디올의농도와비례하는반면, 습관성유산과거력이있는여성에서는난포기와황체기에걸쳐그수가감소하여폐경기여성과비슷하게감소되어있으며그기능또한현저히저하된것을알수있다. 30 Regulated upon activation normal T cell expressed and secreted (RANTES) 는모체의면역조절 T 림프구와 T effector 세포사이의균형을조절하여모체의면역관용을유발하는데습관성유산의과거력이있는환자의말초혈액에서단핵구를추출후 Swan 세포와공배양시 RANTES의기능이발휘하지못하였으며, Treg 세포및 CD3 + annexin-v + 세포의감소및 apoptotic trophoblast 세포의증가를볼수있다. 31 한편, 임신초기에조절 T 림프구는탈락막내의 CD4 + T 림프구의약 20% 를차지하는반면자연유산을경험한환자의탈락막에서는 6% 정도로감소되어있다는보고도있었다. 32 최근의논문들에의하면조절 T 림프구는임신제 1 삼분기의착상부위에그수가확실히증가하는것으로일관되게보고되고있어배아의착상과임신초기에혈관신생및태반의발달에중요한역할을한다는데에는이론의여지가없다. 하지만, 정확한작용기전에대해서는확실한실험적증거가없는상태이며조절 T 림프구및그와관련이언급된면역세포들그리고사이토카인, IDO, toll like receptor (TLR) ligands, chemokine signals 등의분자학적인기전에대한연구가요구된다. 자연살해 T 림프구 (Natural Killer T, NKT cells) 최근의보고에의하면자궁내막과탈락막에서발견되는 Tαβ 림프구의아주적은일부에서 CD56 세포표면항원이발현되며이를자연살해 T 림프구라칭하는데인간탈락막에서전체 T 림프구의 약 0.48% 를차지한다. 33,34 이림프구는비교적흔치않은 T 림프구의한종류로 Th1과 Th2 사이토카인을분비할수있는능력을가지고있으며일반적인 αβ T 림프구가 MHC class-1 like molecule인팹티드를인지하는것과는달리 glycolipid를인지하는특징을가지고있다. 35 NKT 세포는수용체및표면인식자의발현에따라 1형 ( 고전형 ), 2형, 및 NKT- 유사형의세가지로구분된다. 35 NKT 세포의기능은명확하게밝혀지지않았으나탈락막에서 innate와 adaptive 면역반응을모두수행하는것으로보고되었고다양한종류의사이토카인을분비하여면역세포를활성화시키는능력이있다고알려졌다. 34 즉, NKT 세포는수지상세포의 αgalcer를인지후 CD40 ligand가활성화되고이활성화된 CD- 40 ligand와수지상세포의 CD40이결합하여 IL-12 (interleukin-12) 분비를증가시키는기능이있으며그외 B 림프구뿐아니라자연살해세포의활성화에도관여한다. 36 활성화된 NKT 세포는임신에관여하는것으로보고되고있는데, 생쥐실험에서 NKT 세포의자극은유산및조기진통과밀접한관계가있다고보고되기도하였다. 37 즉, C57BL/6J 생쥐모델을이용한실험에서 CD1d ligand αgalcerd의유사체를투여하여 NKT 림프구를자극시임신주수에상관없이유산을유발하며, 유산과관련된 NKT 림프구의역할은임신초기의 perforin, 임신중기이후의 TNF-α, INF-γ 등을분비하는기능에밀접한연관이있는것으로보고되고있다. 37,38 한편, 이전의연구결과와는상반된보고도있었는데, 임신중말초혈액 NKT 림프구는비임신시와비교하여현저하게증가되어있는반면 INF-γ 생산능력은감소하고정상임신과비교하여반복유산환자의말초혈액에서 NKT 림프구가현저하게감소함을보고하였다. 39,40 NKT 세포는 trophoblast에대한공격과연관된다는보고가있는반면, 37 agalcer를통한 NKT 세포의활성화가비장의자연살해세포의활성화를초래하는연구결과와연관하여 NKT 세포와관련된자연임신은자궁내자연살해세포 - 155 -
대한생식의학회지 Figure 4. Hypothetical model of NKT cells in immunemediated pregnancy loss. NKT cells are activated directly by bacterial wall glycolipids, or they can be activated indirectly via LPS or CpG-stimulated APCs. Pathogen derived cell wall glycolopids are endocytosed by an APC and loaded onto CD1d. Pathogen-derived TLR ligands such as LPS trigger TLR4 signaling on as APC (DC and/ or macrophage) which induces loading of endogenous CD1d agonist ligands onto CD1d. Activation of NKT cells through TCR recognition of CD1d and agonist ligand leads to cytokine production and upregulation of CD40L (CD154). Cross-linking of CD40 expressed on the APC by CD40L in turn leads to APC activation and results in secretion of IL-12. IL-12 production leads to NK cell activation and subsequent production of INF-γ and TNF. (Modified from Boyson et al.) 35 Kwang Moon Yang. Roles of T Lymphocytes in Early Human Reproduction. Korean J Reprod Med 2009. (unk cell) 의활성과관련된 transactivation 과정과연관된다는가설도제기되었다. 41 한편, NKT가 knock-out된생쥐에서 Lipopolysaccharide (LPS) 를이용하여면역계를자극시혈청 TNF-α 뿐아니라자연살해세포의 INF-γ의생산이현저하게줄어드는것에근거하여 NKT 세포가 Toll like receptor (TLR) 와 LPS 또는 CpG와의교차반응후나타나는면역반응에중요한작용을한다는새로운기전이제시되기도하였다 (Figure 4). 42 사이토카인분비에따른 T 림프구의분류 CD4 + T 림프구는사이토카인을생산하는주된면역세포로분비하는사이토카인의종류에따라 Th0, Th1, Th2, Th3, 그리고 Th17 림프구로분류된다. Th0 림프구는 naïve T 세포로부터분화되어 Th1 또는 Th2 세포로분화할수있는능력을가진세포로프로게스테론은 Th0 세포를 Th2 세포로분화시키는가장강력한물질로서임신중고농도의프로게스테론에의해 IL-4, IL-5 등 Th2 사이토카인분비를촉진시켜면역관용환경을조장한다. 43 반면배란후황체와탈락막등에서분비되는 relaxin은 IL-4의생성을저하시키지않으며동시에주된 Th1 사이토카인이며혈관신생등에필수적인 INF-γ의생성을촉진시키는작용을한다. 44 결국착상및임신중호르몬의분비는태아-모체간극에서 T0 림프구의분화및사이토카인분비패턴의결정에매우중요한역할을하고있다. Th1 림프구는 INF-γ, IL-2, TNF α 및 β를생산, 분비하며대식세포매개에의한숙주방어에주된역할을한다. 45 이중 TNF-α는 Th2 림프구와 CD8 + cytotoxic T 림프구에서도생성이되지만대부분이 Th1 세포에서생성되므로세포매개면역기전에서의 TNF-α의세포용해작용은일반적으로 Th1-형사이토카인에의한다고인식되고있다. 46 Th2 림프구는 IL-4, IL-5, IL-6, IL-10, IL-13을생산하며, IL-4는 B 림프구에서 IgE, IgG1 항체의생산을자극하고, IL-5는호산구세포의성장과분화를촉진하며, IL- 13, IL-10 등은 IL-4와함께대식세포의기능을억제하는작용을한다. 한편, Th2 림프구는 Th1 세포와는달리숙주의방어기전이대식세포와는독립적인기전으로작용한다. 45 비교적최근 CD4 + T 림프구중 IL-10과 TGF-β 를주로분비하는세포군이발견되었는데이들은억제 / 조절의공통적인특징을가지고있어 T 림프구의증식과기능을억제하며항원-특이적 T 림프구관용 (antigen-specific T-cell tolerance) 에관여한다. 47,48 이들 " 조절성림프구, regulatory T cells", 들은각각의표현형및사이토카인분비능력, 그리고조직기원등에따라제 1 형조절성 T 림프구 (type 1 regulatory T-cells, Tr 1), T helper 3 (Th3), CD4 + CD25 + 면역조절 T 림프구 (Treg cell) 로구분된다. 49 Tr 1-156 -
제 36 권제 3 호, 2009 양광문 림프구는염증성장질환생쥐실험에서 IL-10 분비를통해항원특이적인면역억제기능이있는세포로특징지어졌고, 제 3 형 Th 림프구는 TGF-β의분비를통해면역억제기능을발휘하는세포로특징지어졌다. 48,50 하지만 IL-10 null mutant 생쥐를이용한실험에서동종면역에의한생식부전의결과를증명할수없었고, 51 TGF-β null mutant 생쥐를통한실험에서난자성숙및배란과정에서의 TGF-β의역할과생식면역계와의관계가명확히특징지어지지않아, 52 생식분야에서의 Tr1 림프구와제 3 형 Th3 림프구의역할에대한더많은연구가필요한상태이다. 반면, CD4 + 25 - T 림프구의변형으로여겨지는제 3 형림프구인 Tr 1 림프구와는달리독특한세포 lineage를갖는 CD4 + 25 + 면역조절 T 림프구는면역계에서가장강력하고광범위하게작용하는억제성면역림프구로인정받고있으며, 50 생식과정에필수적인태아에대한모체의면역관용에도적극관여한다는것에대해반론이없다. CD4 + T 림프구와사이토카인네트워크 (T helper cells and cytokine network) Th1 형면역반응과 Th2 형면역반응은각자의사이토카인을통해임신시태아와태반의성장에필요한 Th2 형면역반응이우세한환경을유지하며, 53 반면 Th1 형면역반응의우세현상은태아와태반의성장을저해하며태아의생존을위해서는 Th1 형면역반응과 Th2형면역반응의균형이중요하다. 결국 Th1/Th2 면역반응의균형에는사이토카인이관여하고사이토카인과 T 림프구들간의긴밀하고복잡한 network이형성되어배아의착상및성장과발달에필수적인역할을한다. T 림프구-사이토카인 network은착상과정에서부터이루어지게되는데, 착상이일어난직후 tolerogenic factor인 regulated upon activation normal T cell expressed and secreted (RANTES) 의자극에의해국소적인 Th1 면역반응이일어나게되고그반 응은점차 Th2 면역반응으로이행되게된다. 31 실제로임신첫삼분기의 trophoblast는 IL-1α, IL-1β, TNF-α mrna가감소하고 IL-6, IL-10에대한 mrna 양은증가하며 INF-γ, IL-2 등에관한 mrna의발현은극히미미한현상을발견할수있다. 이런현상들은임신제 1 삼분기에 chorionic villous 조직이대식세포와연관된사이토카인유전자를발현하는양상을보이며이런유전자발현이태아의생존에매우중요한요소라는것을암시한다. 54 모체-태아간접촉면의 Th2 형사이토카인반응은융모막과탈락막에존재하는백혈구들에의해조절된다. 즉, 임신제 1 삼분기에 chorionic villi 에서 IL-4가발현되고 IL-10과 TNF-α 등은 cytotrophoblast가아닌탈락막내백혈구에서발현된다. 55 융모막이제 1 형사이토카인을분비하는자연살해세포 (NK cell) 와 T 림프구를억제한다는것은실험적으로증명되었는데 TNF-α를분비하는자연살해세포를 JEG-3 세포와공배양시융모막세포주와자연살해세포와의세포대세포의직접접촉에의해 TNF-α를분비하는자연살해세포가현저하게감소하는반면, INF-γ, IL-4, IL-10 등을분비하는자연살해세포의숫자에는변화가없음을발견할수있었다. 한편, human leukocyte antigen (HLA)-G가발현된 trophoblast 세포주와공배양시 TNF-α를분비하는자연살해세포를감소시키지는않았다. 56 TNF-α와 INF-γ는자연유산의병인에중요한역할을하는대표적인염증성사이토카인으로, 57,58 생체외실험에서융모막의세포자멸사를유발하고융모막에서 FAS의발현및부착능을증가시킨다. 반면, IL-6과 IL-10은융모막의 FAS-mediated apoptosis에대한저항력을증가시킨다. 59 Fas/Fas 리간드 (Fas/Fas-L) system은세포의증식과재생에관련하여세포자멸사과정에주된역할을하므로융모막에서 Th1 형사이토카인의 Fas의발현및부착능의증가는융모막세포자멸사를촉진하여태아의손실을초래한다. 59 한편, 원인불명의습관성유산환자에서말초혈액단핵구 (peripheral blood monocyte, PBMC) 와탈 - 157 -
대한생식의학회지 락막림프구의 Th1 사이토카인분비에대한많은연구가시행되었다. Raghupathy 등은태반세포와말초혈액단핵구를공배양시상청 (supernatant) 에서 INF-γ 등 Th1 형사이토카인의농도가습관성유산의과거력을가진여성에서대조군에비해유의하게높은반면, IL-6, IL-10 등의사이토카인은대조군에비해유의하게낮음을보고하였고 60 습관성유산환자의말초혈액에서 Th1 사이토카인 (TNF-α) 을분비하는 CD4 + 형 T 림프구의비율이 Th2 사이토카인 (IL-10) 을분비하는 CD4 + 형 T 림프구에비해유의하게높으며혈청내 TNF-α, TNF-β, IL-2 등의농도도유의하게높다는보고들도있다. 61~64 또한, 반복유산의과거력을가진여성들가운데출산에성공한여성은혈청내 IL-6의 Figure 5. Inflammatory/thrombotic process at maternal-fetal junction determines fetal outcome. Pro-inflammatory cytokines secreted by Th1 and type 1 NK cells enhance placental implantation by stimulating angiogenesis and trophoblast invasion. In contrast, excessive pro-inflammatory cytokines induce increased apoptosis of trophoblast cells. Inflammatory responses at the maternal-fetal junction can be induced by thrombophilic conditions (acquired or inherited), systemic autoimmune (antiphospholipid antibody syndrome) or metabolic diseases (hyperglycemia). In addition, autoimmune abnormalities enhance complement activation on trophoblast cells, which leads to trophoblast cell apoptosis. Treg cells and type 2 NK cells counteract inflammatory cytokines through production of anti-inflammatory cytokines and stimulating indoleamine 2,3 dioxygenase (IDO) production. ( ) positive effect; (- - -) negative effect. ANA, antinuclear antibody; APA, antiphospholipid antibody; APS, antiphospholipid syndrome; pnk, peripheral blood NK cells; Th1, T helper 1 cells; Tc1, T cytotoxic cells; Treg, T regulatory cells; unk, uterine NK cells. (Modified from Kwak-Kim et al.) 66 Kwang Moon Yang. Roles of T Lymphocytes in Early Human Reproduction. Korean J Reprod Med 2009. - 158 -
제 36 권제 3 호, 2009 양광문 농도가유의하게증가된반면유산이된여성에서는 TNF-α의농도가유의하게높다는결과가보고되기도하였다. 63 요약착상, 태반생성및임신유지등생식과정에서 semi-allograft인배아및태아가생존하기위해서는모체면역계의면역관용이요구된다. 면역관용은분자생물학적으로염증반응과항염증반응의적절한균형을유지하는인식되고있으며, 생식과정에서모체면역계의 T 림프구, 자연살해세포, 수지상세포, 대식세포등여러면역세포의유기적인협조하에이루어진다. 면역세포들은특정항원및사이토카인의자극에따라정반대의성질을가진사이토카인을생산, 분비할수있는특성을가지고있어각각을염증성또는항염증성면역세포로명확히구분할수없으며면역세포의이러한특성에의해생산및분비되는사이토카인의종류에따라 Th0 형 (Th 0 cell, Tc 0 cell, NK 0 cell), Th1형 (Th 1 cell, Tc 1 cell, NK 1 cell), Th2 형 (Th 2 cell, Tc 2 cell, NK 2 cell), Th 3 형세포 (Th 3 cell, Tc 3 cell, NK 3 cell) 로분류하기도한다. 즉, 착상시기에혈관신생및영양막의자궁내침투를위한적절한염증성사이토카인 (inflammatory cytokine) 의분비및임신의지속을위한항염증성 (anti-inflammatory) 사이토카인의분비등생식과정에서수반되는염증성과항염증성면역반응의적절한균형을유지하는기전은특정면역세포만의작용으로결론지을수없으며면역세포간 network의산물이라할수있다 (Figure 5). 면역세포중최근그존재가알려진면역조절 T 림프구 (T reg cell) 는여러연구자들에의해면역관용에관여함이일관되게보고되고있어자궁내모체-태아간접촉면에서면역세포들간의 network 에중추적인역할을할것으로인식되고있으나작용기전으로제시되고있는가설들을뒷받침할만한객관적인연구가필요한실정이다. 본고찰에서는착상과임신유지등생식과정에수반되는면역세포및그세포들의작용기전중 T 림프구의역할에중점을두고그분류및기능에대해정리해보았다. 결론적으로착상과임신의유지등생식과정에서 T 림프구는면역관용과거부에적극적으로작용하며착상부전, 습관성유산등면역학적병인이유사한생식장애 (poor reproductive performance) 들의발병에중요한역할을하는것은의심할여지가없다. 하지만향후 T 림프구및그와연관된면역세포들의작용에대한확실한분자학적규명이요구된다. 참고문헌 1. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature 1953; 172: 603-6. 2. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 2004; 5: 266-71. 3. Piccini MP. T-cell cytokines in pregnancy. Am J Reprod Immunol 2002; 47: 289-94. 4. Wilczynski JR. Immunological analogy between allograft rejection, recurrent abortion and pre-eclampsia - the same basic mechanism? Hum Immunol 2006; 67: 492-511. 5. Johnson PM, Christmas SE, Vince GS. Immunological aspects of implantation and implantation failure. Hum Reprod 1999; 14 Suppl 2: 26-36. 6. Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D. Granulated lymphocytes in human endometrium: histochemical and immunohistochemical studies. Hum Reprod 1991; 6: 791-8. 7. Vassilidou N, Bulmer JN. Quantitative analysis of T lymphocyte subsets in pregnant and nonpregnant human endometrium. Biol Reprod 1996; 55: 1017-22. 8. Athanassakis I, Bleackley RC, Paetkau V, Guilbert L, Barr PJ, Wegmann TG. The immunostimulatory effect of T cells and T cell lymphokines on murine fetally derived placental cells. J Immunol 1987; 138: 37-44. 9. Chaouat G, Menu E, Athanassakis I, Wegmann TG. Maternal T cells regulate placental size and fetal survival. Reg Immunol 1988; 1: 143-8. - 159 -
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